Valve Disease and Diet Pills—Where Do We Stand?

Obesity is a common condition in adults and has significant cardiovascular consequences. Several pharmacologic agents have been approved by the U.S. Food and Drug Administration (FDA) for the short-term single-drug treatment of obesity, including phentermine (Adipex, Fastin, Ionamin), fenfluramine (Pondimin) and dexfenfluramine (Redux). Fenfluramine and its isomer, dexfenfluramine, are thought to act by affecting brain serotonin levels.

Recently, the combination of fenfluramine and phentermine (fen/phen) has come into widespread use, with an estimated 14 million prescriptions written for either fenfluramine or dexfenfluramine since 1995.1 Much concern has been generated by recent reports linking valvular heart disease with the use of fenfluramine and phentermine in combination.2–4 In July 1997, researchers at the Mayo Clinic reported 24 cases of valvular heart disease in women who were treated with the combination of fenfluramine/phentermine.2 These patients were treated for a mean duration of 12.3 months (range: one to 28 months). Twenty of the 24 patients had cardiovascular symptoms, and four had a new heart murmur only. Both left- and right-sided valvular lesions were observed; either the mitral valve or the aortic valve was involved in all of the cases, and two or more valves were affected in 71 percent of the cases. The echocardiographic features of the valvulopathy included thickening and diastolic doming of the anterior mitral valve leaflet, thickening of the subvalvular apparatus and tethering of the posterior leaflet. The regurgitation appeared to be the result of malcoaptation of the leaflets. The histopathologic features were similar to those seen in carcinoid valvular disease, which usually affects the tricuspid and pulmonic valves, and in ergot alkaloid–induced valvular disease.5

The authors2 hypothesized that high circulating levels of serotonin are related to the valvulopathy, since ergot valvulopathy, carcinoid valve disease and valvulopathy related to diet drugs have this factor in common. It is important to underscore the limitations of this study. As the authors acknowledge, this paper was an initial description of a clinical association and not an epidemiologic study or even a case-control study. Therefore, the study does not address the issue of incidence or prevalence of valvulopathy.

Preliminary, unpublished data were made available on the World Wide Web by the FDA and bear review, since these data were the basis of the FDA's decision to seek withdrawal of fenfluramine and dexfenfluramine from the U.S. market. These data were recently summarized in a report from the Centers for Disease Control and Prevention (CDC).6 They are taken from echocardiographic reports in five independent echocardiographic prevalence surveys of patients who had received dexfenfluramine or fenfluramine alone or in combination with phentermine. The prevalence of patients meeting the FDA criteria for valvulopathy (greater than or equal to mild aortic regurgitation, or greater than or equal to moderate mitral regurgitation) was substantial—31.7 percent (26.2 percent to 37.6 percent). The percentage of patients in these surveys with symptoms or signs of valvular disease accompanying echocardiographic abnormalities is not yet known.

The 31.7 percent prevalence of significant valvulopathy by the FDA criteria appears to be higher than what would be expected in the general population. While trivial (and likely clinically insignificant) valvular regurgitation by color flow Doppler is common, greater degrees are less common, particularly in subjects who are under 50 years of age. In the study by Klein and colleagues,4 61 normal volunteers aged 20 to 49 years were examined; mitrial regurgitation graded as “trivial” was found in all subjects, but “mild” regurgitation was not encountered in any subject. No normal subject had any degree of aortic regurgitation. In the group of 61 normal subjects aged 50 to 82 years who were studied by the same authors, trivial degrees of regurgitation were much more common (64 percent for the mitral valve and 38 percent for the aortic valve) and mild regurgitation was also common (36 percent for mitral and 62 percent for aortic).4 No normal subject was found to have regurgitation in excess of the “mild” grade.

A much larger data set has been published in abstract form by the CARDIA (Coronary Artery Risk Development in Young Adults) investigators.7 In this study of 4,352 healthy adults aged 23 to 35 years, mitral regurgitation was found in 10.9 percent of subjects and was judged to be mild in 93.0 percent; the corresponding incidence for aortic regurgitation was 1.2 percent and was judged to be mild in 79.0 percent.7 Very little data exist concerning the prevalence of Doppler abnormalities in obese subjects.

What Is Not Known. As stated above, very little is known about the following:

The incidence of new significant valvular disorders associated with fenfluramine/dexfenfluramine. The answer to this question will come from case-control studies and smaller retrospective studies using patients as their own control subjects.

The risk factors for developing valvulopathy.

Whether the valve abnormalities are reversible if the drugs are discontinued.

Given the importance of this issue and the widespread availability of echocardiography, it is likely that data will emerge in the near future that will provide answers to these and other related questions.

Who Should Undergo Echocardiography? Patients and physicians are wondering which patients treated with fenfluramine, dexfenfluramine alone or in combination with phentermine should undergo echocardiography. At this point, a precise answer to this question cannot be given. Recent guidelines published by the American College of Cardiology/American Heart Association Task Force on Echocardiography, a consensus panel, emphasize that echocardiography is indicated in a patient with a heart murmur and cardiorespiratory symptoms or someone without symptoms who has a murmur if the clinical features indicate a moderate probability of cardiovascular disease. At this point, it seems that the most prudent course of action is for patients to contact their physicians and arrange for a physical examination. Ideally, a physical examination should be sufficient to indicate the presence or absence of significant valvular dysfunction. According to the CDC report,6 however, murmurs were heard in only 17 percent of patients with valvular regurgitation meeting the FDA criteria for valvulopathy. Therefore, an echocardiogram is appropriate if the patient's body habitus precludes an adequate examination.

Endocarditis Risk. The extent to which patients exposed to these drugs are at risk of bacterial endocarditis is not known. Therefore, the physician may recommend that the individual receive an antibiotic before undergoing dental or surgical procedures likely to introduce certain bacteria into the bloodstream,8 or to postpone elective procedures until the risk of endocarditis can be ascertained by examination or by echocardiography. For emergency procedures that must be performed before a cardiac evaluation is completed, empiric antibiotic prophylaxis should be administered according to the guidelines of the American Heart Association.8

Dr. Aurigemma is the director of noninvasive cardiology at the University of Massachusetts Medical Center and associate professor of medicine and radiology at the University of Massachusetts Medical School, Worcester. Dr. Gaasch is director of cardiovascular research at the Lahey-Hitchcock Medical Center, Burlington, Mass., and professor of medicine at the University of Massachusetts Medical School.